AUTHOR INFORMATION

Section 1 of 11

Authored by Steven K Bergstrom, MD, Assistant to the Chairman, Department of Pediatrics, Division of Hematology-Oncology, Kaiser Permanente Medical Center of Oakland, CA

Steven K Bergstrom, MD, is a member of the following medical societies: Alpha Omega Alpha, American Society of Hematology, and American Society of Pediatric Hematology/Oncology

Edited by Stephan A Grupp, MD, PhD, Director, Stem Cell Biology Program, Children's Hospital of Philadelphia; Assistant Professor, Department of Pediatrics, Division of Oncology, University of Pennsylvania; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Timothy P Cripe, MD, PhD, Associate Professor of Pediatric Hematology/Oncology, University of Cincinnati; Director, Translational Research Trials Office, Department of Pediatrics, Cincinnati Children's Hospital Medical Center; Helen SL Chan, MBBS, FRCP(C), FAAP, Senior Scientist, Research Institute; Professor, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Canada; and Max J Coppes, MD, PhD, MBA, Executive Director, Center for Cancer and Blood Disorders, Children's National Medical Center

Author's Email:	Steven K Bergstrom, MD
Editor's Email:	Stephan A Grupp, MD, PhD

eMedicine Journal, April 11 2006, VOLUME 7, Number 4

INTRODUCTION

Section 2 of 11

Background: Patients with an unusual complex of congenital developmental abnormalities such as aniridia, genitourinary (GU) malformations, and mental retardation are at high (>30%) risk of having a Wilms tumor. The association is aniridia, GU malformations, and mental retardation (AGR) syndrome if Wilms tumor is absent and Wilms tumor, aniridia, GU malformations, and mental retardation (WAGR) syndrome if Wilms tumor is present. These syndromes result from the loss of chromosomal material from the short arm of chromosome 11.

Aniridia, GU malformations, and/or mental retardation are usually detected in the perinatal period, and patients with these conditions require careful long-term follow-up, both because of the consequences of the congenital defects and because of the potential development of a Wilms tumor. Early tumor detection has improved the long-term disease-free survival of children with WAGR syndrome.

Pathophysiology: WAGR syndrome affects the development of seemingly disparate areas of the body, including the kidney, the GU system, the iris of the eye, and the central nervous system (CNS). The deletion of varying lengths of chromosomal material along the short arm of chromosome 11 is the underlying defect, and developmental abnormalities are related to the contiguous loss of neighboring genes. The constitutional loss of one allele of the Wilms tumor suppressor gene (WT1) results in GU anomalies and forms the first of 2 genetic events in the development of a Wilms tumor. Alterations to the remaining allele result in the development of a Wilms tumor, usually in early childhood. Meanwhile, the deletion of one copy of the PAX6 gene is responsible for aniridia. PAX6 plays a role in central nervous system development as well and may be responsible for the mental retardation seen in a reported 75% of children with WAGR syndrome.

Frequency:

• In the US: The incidence of WAGR syndrome has not been determined.

  Wilms tumor occurs in approximately 8 per 1 million white children in the United States; the incidence is somewhat higher in blacks. Only 2% of patients with Wilms tumor have an associated genetic disorder.

  In a US study of 3442 patients with Wilms tumor, only 26 (0.76%) presented with aniridia.

  Wilms tumor occurs in more than 30% of patients with 11p13 deletions.

Mortality/Morbidity:

• Wilms tumor: The overall survival rate of patients with Wilms tumor is excellent and related to the histologic features of the tumor (favorable vs unfavorable) and the stage of the disease. In stage I, the disease is localized to the kidney. In stage II, the disease extends through the capsule of the kidney. In stage III, the disease extends to ipsilateral structures or beyond the line connecting the poles. In stage IV, the distinct metastases are present. In stage V, bilateral kidney involvement is present.
  
  In the third National Wilms Tumor Study (NWTS), the survival rate ranged from 95% for stage I to almost 80% for stage IV. Patients with stage V tumors, some of whom had WAGR syndrome, had an overall survival rate of approximately 87%.

• Aniridia: Aniridia results in decreased visual acuity, although the amount of vision loss is variable. Aniridia has been associated with the development of glaucoma, probably due to the structural abnormalities of the anterior chamber of the eye. Cataracts have also been reported in these patients.

• GU abnormalities: A large spectrum of GU abnormalities is associated with WAGR syndrome; these include cryptorchidism, hypospadias, and renal and ureteral malformations. Streak ovaries and bicornuate uterus have been reported in females with AGR syndrome. The presence of pseudohermaphroditism should alert the clinician to the possibility of Denys-Drash syndrome, a distinct diagnosis resulting from constitutional WT1 mutations.
  
  
• Mental retardation: The cognitive function of patients with WAGR syndrome is highly variable. The appearance of retardation is correlated with the amount and position of genetic material lost from chromosome 11. Cognitive testing must be performed carefully and is more difficult to evaluate in children with vision loss.

CLINICAL

Section 3 of 11

History: Symptoms suggestive of AGR syndrome are usually noted in the perinatal period.

• The mother's pregnancy and the patient's birth history are generally unremarkable.



• Nephromegaly may be on the prenatal ultrasonogram.



• The family history is rarely contributory.



• Aniridia and/or GU abnormalities are usually detected while the baby is in the newborn nursery, and the diagnosis of AGR syndrome is considered at that time.

Physical:

• Wilms tumor


• • The development of Wilms tumor in patients with WAGR syndrome has a more rapid time course than of a sporadic Wilms tumor. In one cohort, the average age of tumor diagnosis was 17-27 months compared with 38 months in non-WAGR patients.
  
  
  
  • If AGR syndrome has been diagnosed, the tumor may be detected with routine ultrasonographic screening. Otherwise, the presence of a new or enlarging abdominal mass, hematuria, abdominal pain, or hypertension may indicate the development of malignancy.
  
  
  
  • A palpable mass that is located in either flank and immobile on respiration is suggestive of a Wilms tumor.
  
  
  
  • Occasionally, patients may have a varicocele, which is due to obstruction of the spermatic vein by a thrombus in the inferior vena cava.
  
  
  
• Aniridia


• • The congenital absence of the iris is usually the first and most striking feature.
  
  
  
  • Although generally absent in the newborn period, scanning nystagmus may be present in infancy.
  
  
  
  • The degree of vision loss varies among patients.
  
  
  
• GU abnormalities


• • A range of GU abnormalities may be present at birth.
  
  
  
  • Cryptorchidism and hypospadias are commonly observed in association with AGR and WAGR syndromes.
  
  
  
  • The presence of pseudohermaphroditism should alert the clinician to the possibility of Denys-Drash or Frasier syndromes, both of which result from mutations in the WT1 gene.
  
  
  
  • Nephroblastomatosis, or the enlargement of one or both kidneys related to the presence of nephrogenic rests, may be detected by means of prenatal ultrasonography or careful palpation of the abdomen during the neonatal period.
  
  
  
• Mental retardation


• • The presence and degree of mental retardation vary greatly among patients with WAGR syndrome.
  
  
  
  • Generally, determining the degree of retardation is impossible in the newborn period, although parents should be alerted to the possibility.
  
  
  
  • As the patient ages, the reliability of neuropsychometric testing improves, and baseline testing should be performed.
  
  
  
  • The presence of vision loss may complicate the testing process because children with vision difficulties may acquire developmental milestones differently from children with normal vision. Thorough developmental screening appropriate in individuals with visual impairment, and it is required for the diagnosis of mental retardation.
  
  
  

Causes: WAGR syndrome is caused by the contiguous loss of chromosomal material from the short arm of chromosome 11.

• Knudson postulated that the appearance of early bilateral disease in some children suggests the possibility that these patients have a constitutional genetic defect that predisposes them to the development of a Wilms tumor. The prezygotic loss of one of the alleles is followed by the loss of the second allele in infancy or early childhood (somatic).



• The identification of the gene responsible for Wilms tumor did not occur until 1990, when 3 groups independently identified the WT1 gene on band 11p13.


• • The genetic structure includes 4 zinc-finger regions, which suggest that WT1 may be important in controlling the expression of other genes. Both the GU abnormalities and the development of a Wilms tumor in patients with WAGR syndrome are related to the loss of WT1 gene function. In adults, WT1 isoforms continue to be expressed in some kidney tissue.
  
  
  
  • A neighboring gene, PAX6, is responsible for the development of the iris. Deletion of the PAX6 gene as part of the band 11p13 deletion in patients with AGR or WAGR syndrome results in aniridia.
  
  
  
  • Deletion of the PAX6 gene, which plays a role in myelinization of the cerebral hemispheres during CNS development, may also be responsible for the mental retardation seen in the (W)AGR association. An association between PAX6 abnormalities and diabetes may indicate that it plays a role in pancreatic development as well.
  
  
  

DIFFERENTIALS

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Denys-Drash Syndrome
Genital Anomalies
Wilms Tumor

Other Problems to be Considered:

Fraser syndrome
Aniridia

WORKUP

Section 5 of 11

Lab Studies:

• Blood urea nitrogen (BUN) and/or creatinine levels should be assessed.


• • Renal function is rarely affected by nephroblastomatosis alone.
  
  
  
  • GU abnormalities may lead to reduced renal function early in life.
  
  
  
• Findings of protein in the urine should alert the clinician to the possibility of Denys-Drash or Frasier syndromes, which are associated with declining renal function. Blood may be present in the urine when patients present with a Wilms tumor.



• A complete blood count with a platelet count may demonstrate anemia due to blood loss secondary to an enlarging renal mass.



• Serum calcium levels should be measured.



• Cytogenetic testing should be performed to confirm the diagnosis. Standard high-resolution chromosome studies may not be able to detect deletions in WT1. The addition of molecular cytogenetic fluorescence in situ hybridization techniques may define the extent of the deletion.

Imaging Studies:

• Renal ultrasonography is the study of choice to confirm the diagnosis of renal pathology in the neonatal period.


• • Enlargement of the kidneys usually suggests nephroblastomatosis. The appearance of both kidneys should be documented.
  
  
  
  • Some (internal) GU abnormalities are usually best documented by means of ultrasonography, although additional imaging tests may be required.
  
  
  
  • A follow-up examination of the kidneys should be performed every 3 months until the patient is aged 7 years. Physical examinations should be performed every 6 months until the patient's growth is complete. Baseline CT may be indicated at the time of the initial diagnosis.
  
  
  
  • The presence of an enlarging renal mass suggests the development of a Wilms tumor.
  
  
  
  • Evaluation of the renal vein and inferior vena cava for the presence of tumor thrombi is important for staging, and the study is usually accomplished by means of renal ultrasonography and/or Doppler imaging.
  
  
  
• Chest radiography becomes important in the staging workup once Wilms tumor is diagnosed.



• CT of the chest and abdomen may provide further information about the location and stage of the tumor.

Procedures:

• The role of a renal biopsy at the time of diagnosis of WAGR syndrome in the neonatal period is controversial.



• The presence of nephrogenic rests can be demonstrated histologically, but the risk of losing renal function as a result of the procedure may outweigh the need to confirm the diagnosis in a patient with AGR syndrome.



• Transcutaneous renal biopsy has no role in the diagnosis of a Wilms tumor.

TREATMENT

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Medical Care:

• Urology: After AGR or WAGR syndrome is diagnosed, GU abnormalities must be evaluated immediately, and the patient should be referred to a pediatric urologist.



• Genetics: Although the abnormality associated with WAGR syndrome may not be demonstrated by means of routine cytogenetic tests, the geneticist can help in assessing the 11p13 region using fluorescent in situ hybridization techniques. He or she can consult with the family regarding the likelihood of their having other affected offspring, and the geneticist can consult with patients regarding the risks to their offspring.



• Oncology: Once a Wilms tumor is diagnosed in a patient with WAGR syndrome, the services of a pediatric oncologist are required for treatment and follow-up.

Surgical Care: Specific urologic intervention may be required early in patients with the AGR syndrome. However, if a Wilms tumor develops, a multidisciplinary approach is required prior to surgery.

Consultations:

• A pediatric ophthalmologist should be consulted early in the course of the disease to evaluate the ocular deformity, and this ophthalmologist should follow-up with the patient for long-term consequences (eg, vision loss, potential cataract development).



• The potential for developmental delay in children with AGR or WAGR syndrome requires early evaluation and intervention by a pediatric developmental specialist. On the basis of the findings from this evaluation, children with vision impairment and mental retardation can be appropriately referred to community resources.

MEDICATION

Section 7 of 11

Medical treatment of patients with WAGR syndrome depends on the appearance of Wilms tumor. The histologic features and the stage of the tumor determine the appropriate chemotherapeutic course. Refer to a pediatric oncologist for the most current chemotherapeutic regimen.

FOLLOW-UP

Section 8 of 11

Further Outpatient Care:

• Oncologic follow-up care: After initial evaluation and treatment, the long-range plan for children with WAGR syndrome is regular follow-up.


• • Abdominal ultrasonography should be performed every 3 months to examine the kidneys for the development of a Wilms tumor. The age at which these tests may be discontinued has not been established, although the general recommendation is to continue until the patient is aged 7 years.
  
  
  
  • In Beckwith's report of a cohort of 61 patients with WAGR syndrome, the oldest patient in whom Wilms tumor developed was aged 7 years 3 months. Of the patients in whom tumors ultimately developed, 98% received the diagnosis before their seventh birthday. Recent reports of patients with AGR syndrome who develop Wilms tumor later in life, one of whom developed Wilms at age 25 years, suggest that further follow-up, by either physical examination or ultrasonography, may be recommended for older patients.
  
  
  
• Ophthalmologic follow-up care: Patients with WAGR syndrome require routine ophthalmologic follow-up, both to evaluate and maximize their vision and to detect glaucoma.



• Nephrologic follow-up care: Patients with WAGR syndrome appear to have an increased risk of renal failure, which develops over many years.


• • Long-term follow-up should include a regular evaluation of renal function with urinalysis and assessment of blood pressure and BUN and creatinine levels. Renal ultrasonography should be considered if abnormalities are suspected. Rare WAGR patients may develop focal segmental glomerular sclerosis with or without the development of Wilms tumor.
  
  
  
  • Patients with Denys-Drash and Frasier syndromes have long been known to be at an increased risk for renal failure.
  
  
  
  • The NWTS found that the incidence of renal failure is 38% in patients with aniridia and Wilms tumor, compared with only 21 cases in 5358 patients without characteristic congenital GU abnormalities.
  
  
  
  • In one cohort of 54 patients with WAGR syndrome, 14 patients had some level of renal failure. This suggests that renal failure is not only related to the loss of kidney tissue in these patients. Some of them had focal segmental glomerular sclerosis (FSGS) unrelated to the development of Wilms tumor.
  
  
  
  • The underlying reason for renal dysfunction may be multifactorial.
  
  
  

Prognosis:

• Patients with WAGR syndrome have an excellent prognosis for long-term survival. Morbidity and mortality associated with late development of renal failure may be more significant than Wilms tumor.



• Life-limiting abnormalities include GU anomalies in the first year of life.



• Lifelong disabilities may include vision loss and mental retardation.



• In the approximately 30% of AGR patients in whom a Wilms tumor develops, the prognosis is related to the histologic features and the stage of the tumor.



• Early detection seems to improve the outcome.

MISCELLANEOUS

Section 9 of 11

Medical/Legal Pitfalls:

• The main problem for caregivers of patients with WAGR syndrome is infrequent or inappropriate follow-up.



• The failure to perform screening at the recommended intervals and, thus, the failure to diagnose a Wilms tumor in a timely fashion could lead to a more complicated course and to medicolegal difficulties.

TEST QUESTIONS

Section 10 of 11

CME Question 1: A physician is asked to examine a newborn in the nursery because the nurse noted an abdominal mass. On examination, the patient appeared to have cryptorchidism and aniridia. The physician considers a diagnosis of WAGR syndrome. Which of the following most likely explains the presence of an abdominal mass in a newborn with Wilms tumor, aniridia, genitourinary malformations, and mental retardation (WAGR) syndrome?

A: Duplication of the gastrointestinal (GI) tract
B: Stool in the descending colon
C: Kidney enlarged by nephroblastomatosis
D: Wilms tumor
E: Retroperitoneal lymphadenopathy

The correct answer is C: Neonates in whom WAGR syndrome has been diagnosed may have abnormalities of the eye (aniridia), genitourinary tract (usually cryptorchidism, but hydronephrosis is a possibility), and mental retardation. The precursor lesion of the Wilms tumor, namely, the nephrogenic rest, may be present in amounts that cause nephromegaly. Among those presented in the question, the nephrogenic rest is the most common lesion associated with WAGR syndrome. GI abnormalities are not described with WAGR syndrome. Stool in the colon may be a commonly appreciated cause of an abdominal mass, but it is not associated with WAGR syndrome. Although a Wilms tumor is associated with WAGR syndrome, it does not appear in the neonatal period. Additionally, although retroperitoneal lymphadenopathy is appreciated in the newborn in rare cases, this disorder is not associated with WAGR syndrome.

CME Question 2: A physician has been following up a patient with Wilms tumor, aniridia, genitourinary malformations, and mental retardation (WAGR) syndrome with serial ultrasonography. The patient is now aged 10 years. How often should this patient return to the physician's clinic for screening ultrasonography of the abdomen?

A: The schedule of every 3 months should be continued into adulthood.
B: Screening may be discontinued at this point.
C: The patient should undergo yearly ultrasonographic screening.
D: Because the child is now 10 years old, yearly CT should replace ultrasonography.
E: The patient was never a candidate for ultrasonographic screening.

The correct answer is B: After initial evaluation and treatment, the long-range plan for children with WAGR syndrome is regular follow-up. Abdominal ultrasonography should be performed every 3 months to examine the kidneys for the development of a Wilms tumor. The age at which these tests may be discontinued has not been established, although the general recommendation is to continue until the patient is aged 7 years. In one report of a cohort of 61 patients with WAGR syndrome, the oldest patient in whom Wilms tumor developed was aged 7 years 3 months. Of the patients in whom tumors ultimately developed, 98% received the diagnosis before their seventh birthday.

The answer to this question factors in a large safety zone, although many clinicians feel comfortable stopping the evaluations much earlier. CT has no role as a screening tool, although it can provide some information in patients in whom a Wilms tumor has already developed. Longer intervals between screening tests are not supported by the clinical data.

Pearl Question 1 (T/F): A single-base substitution is responsible for the abnormalities in Wilms tumor, aniridia, genitourinary malformations, and mental retardation (WAGR) syndrome.

The correct answer is False: WAGR syndrome results from abnormalities in the gene located at band 11p13. These abnormalities involve the loss of contiguous areas of genetic material spanning a number of genes, including WT1, PAX6, and possibly others as well. Single-base mutations are more likely to be associated with Denys-Drash syndrome than other mutations.

Pearl Question 2 (T/F): The aniridia associated with Wilms tumor, aniridia, genitourinary malformations, and mental retardation (WAGR) syndrome may result in significant visual impairment.

The correct answer is True: Visual acuity is usually decreased in patients with aniridia related to WAGR syndrome. The amount of vision loss can vary. Furthermore, because of abnormalities in other structures of the anterior chamber of the eye, glaucoma can occur in patients with aniridia.

Pearl Question 3 (T/F): The appearance of Wilms tumor in a patient with Wilms tumor, aniridia, genitourinary malformations, and mental retardation (WAGR) syndrome is always associated with a poorer prognosis than that of patients with a Wilms tumor but not the associated chromosomal abnormality.

The correct answer is False: The prognosis for a patient with a Wilms tumor is based on the histologic features of the tumor and the stage of the disease. Patients with WAGR syndrome are treated in a fashion identical to that of children with a Wilms tumor with similar histologic features and a similar stage. The prognosis does not differ in the patients described.

Pearl Question 4 (T/F): A delay in the normal developmental milestones in a patient with Wilms tumor, aniridia, genitourinary malformations, and mental retardation (WAGR) syndrome almost always indicates mental retardation.

The correct answer is False: Children with WAGR syndrome may have mental retardation due to their chromosomal abnormality. The degree of retardation varies considerably. However, children with vision difficulties may acquire developmental milestones differently from those with normal vision. Thorough developmental screening appropriate in individuals with visual impairment, and it is required for the diagnosis of mental retardation.

BIBLIOGRAPHY

Section 11 of 11

• Beckwith JB: Precursor lesions of Wilms tumor: clinical and biological implications. Med Pediatr Oncol 1993; 21(3): 158-68[Medline].
• Call KM, Glaser T, Ito CY, et al: Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell 1990 Feb 9; 60(3): 509-20[Medline].
• Fischbach BV, Trout KL, Lewis J, et al: WAGR syndrome: a clinical review of 54 cases. Pediatrics 2005 Oct; 116(4): 984-8[Medline].
• Knudson AG, Strong LC: Mutation and cancer: a model for Wilms' tumor of the kidney. J Natl Cancer Inst 1972 Feb; 48(2): 313-24[Medline].
• Little M, Wells C: A clinical overview of WT1 gene mutations. Hum Mutat 1997; 9(3): 209-25[Medline].

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